The present invention relates to a novel process for the preparation of 5-carboxyphthalide, a starting material for the manufacture of the well-known antidepressant drug citalopram, 1-[3-(dimethylamino)propyl]-1-(4fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile.
Citalopram is a selective serotonin reuptake inhibitor which has successfully been marketed as an antidepressant drug for some years, It has the following structure: 
and it may be prepared by the process described in U.S. Pat. No. 4,650,894 according to which 5-cyanophthalide is subjected to two successive Grignard reactions, i.e. with 4-fluoro-phenyl magnesium halogenide and N,N-dimethylaminopropyl magnesium halogenide, respectively, and the resulting dicarbinol compound is subjected to a ring closure reaction by dehydration. The 5-cyanophthalide may in its turn be obtained by reaction of 5-carboxyphthalide with a dehydrating agent and a sulfonamide of the formula H2N-SO2-R wherein R is NH2, alkyloxy, optionally substituted phenyloxy, or substituted phenyl in order to obtain 5-cyanophthalide, cf. our co-pending Danish patent application No. PA199801718.
5-Carboxyphthalide has been described as a useful intermediate in the polymer and paint industry. However, no reliable commercial source is available at present. A known process comprises catalytic hydrogenation of trimellithic acid (DE-A1 2630927). This process provides a mixture of the 5- and 6-carboxyphthalides and, accordingly, it requires elaborate and costly purification. According to J. Org. Chem. 1970, 35, p. 1695-1696, 5-carboxyphthalide is synthesised by reaction of terephthalic acid with trioxane in liquid SO3. During this process, trioxane sublimates and precipitates thereby obstructing the equipment.
Though a number of other methods failed, it has now been found that 5-carboxyphthalide may be prepared from terephthalic acid in high yields by a convenient, cost-effective procedure.
Accordingly, the present invention provides a process for the manufacture of 5-carboxyphthalide 
comprising reaction of terephthalic acid 
with paraformaldehyde, HO(CH2)nH, in oleum.
By the process of the invention, 5-carboxyphthalide is obtained with very high purity and in high yields ( greater than about 75%). Furthermore, as compared with the prior art process (J. Org. Chem. 1970, 35, p. 1695-1696), the process of the invention takes place without precipitation of sublimated trioxane which obstructs the equipment e.g. by precipitating in condensers.
The oleum used is commercially available oleum. So the following are available from Aldrich/Fluka:
12-17% SO3 (Fuming sulfuric acid)=15% oleum
18-24% SO3 (Fuming sulfuric acid)=20% oleum
27-33% SO3 (Fuming sulfuric acid)=30% oleum
From other sources 20% oleum contains 20-25% SO3 
In the method of the invention, the terephthalic acid is condensed with paraformaldehyde liberating water, which reacts with the SO2. When the reaction is complete, 5-carboxyphthalide may be isolated as follows: The reaction mixture is hydrolysed with water. The condensed product, 5-carboxyphthalide inclusive possible diphthalide impurities may then be filtered off, and the 5-carboxyphthalide may be dissolved in aqueous medium by adjusting pH to about 6.7 to 7.3, leaving possible diphthalide impurities in the solid phase. The diphthalide present may be filtered off whereupon 5-carboxyphthalide may be precipitated by acidification, filtered off, washed with water and dried.
Preferably 1.0-1.33 equivalents CH2O and 1.0-2.5, preferably 1.0-2.0 are used. More preferably 1.25-1.5 equivalents SO3 per equivalent terephthalic acid are used. Most preferably, about 1.37 equivalents (corresponding to about 3.3 kg 20-25% oleum/kg terephthalic acid) are used per equivalent terephthalic acid.
The reaction of terephthalic acid with paraformaldehyde is carried out at elevated temperature, conveniently at about 50-148xc2x0 C., preferably 115-125xc2x0 C. or 138-148xc2x0 C. The reaction time is not critical and may easily be determined by a person skilled in the art, a reaction time of 17-21 hours is preferably used for a 210 kg batch at 115-125xc2x0 C. The time is decreased with increasing temperature.
The adjustment of pH to 6.3 to 7.3 in order to dissolve the 5-carboxyphthalide formed may be effected by NaOH, e.g. about 10% aqueous NaOH.
Acidification in order to precipitate the 5-carboxyphthalide may be carried out by adding sulphuric acid until pH=2.
The terephthalic acid used as a starting material is commercially available.